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Review Seizure/Convulsion Review Abuse Liability Review Seizure/Convulsion Review Abuse Liability Mary Jeanne Kallman PhD, DSP Director Global Nonclinical Neuroscience Covance Laboratories Facts About Seizure/Convulsion FDA considers convulsion an “Adverse Effect” - 10 X Margin Convulsion refers to the overt behavioral event while seizure refers to the electrical changes in brain (Behavioral false positives). EEG required to corroborate behavioral report EEG is a multi-unit recording EEG is the translatable clinical measure Usually an issue resolution endpoint Therapeutic compounds with seizure liability at clinical doses Need clinical testing plan – including subject exclusion, understanding therapeutic population, monitoring Different Applications for Seizure Liability/EEG Testing Screening for efficacy – Treatment of epilepsy – Treatment of sleep disorders (sleep onset, sleep duration, % REM) Qualification of normal EEG activity (absence of spiking for animals assigned to tox studies Screening for compound specific safety – Verification of observational report of convulsion (concordance of convulsion and seizure) – Identification of NOAEL (identification of no-effect dose) – *Translational/Issue Resolution study1 Models For Testing Efficacy Models – Kindling, PTZ or other convulsion - precipitated models (Racine scale, observation, actual EEG recording) Screening Animals for Tox Studies, NOAEL Identification and Concordance Assessments - Typically acute EEG recordings from animals in a sling or chair with surface or needle electrodes. No surgery required Translational/Issue Resolution Studies – Continuous EEG with observation and video/ surgical implantation of electrodes for recording Differences Between Acute and Chronic EEG Recordings Acute Recordings Chronic Recordings No surgical implantation Surgical implantation – No mapping of sites surface or deep electrodes Restrained animal Can map sites Short duration recording No restraint Identification of seizure 24/7 up to 3 months or more activity/spiking no Identification of seizure pharmaco-EEG or staging activity/spiking, pharmaco- qEEG EEG, staging, and qEEG More diagnostic rather than Focus on time expansive time expansive recordings Rodent Capabilities Convulsive Liability (PTZ Infusion) – Infusion pumps deliver 10 mg/mL PTZ at a constant rate of 0.5 mL/minute until a clonic convulsion is noted in the animal or for a maximum of four minutes – The following formula is used to convert infusion time to mg/kg dose of PTZ administered: mg/kg PTZ = (Infusion time) (mL/min) (mg PTZ/mL) (1000g) (60 seconds) (Animal weight in g) Telemetric EEG and EMG Assessment Rat and Dog Animal Models Non-tethered telemetrized animals ensure high quality behavioral data – Continuous 24-hour data collection with concomitant video recording to corroborate EEG and EMG events indicative of seizure or convulsion across the animal’s circadian cycle – Qualitative and quantitative assessment, including spectral analysis if valuable – Preclinical EEG analysis provides a description of the progression to seizure across time with repetitive dosing of a compound that can be applied to clinical testing Typical progression of EEG recordings EEG bursting (↑ frequency and amplitude) Series of isolated sharp waves EEG bursting (↑ frequency, amplitude and duration) Seizure (markedly ↑ frequency, amplitude and duration) Review Abuse Liability Controlled Substance Staff (CSS) at FDA Dedicated group that serves as the CDER, FDA and DHHS focus for activities regarding drug scheduling, abuse and dependence • Writes the 8-factor analyses (recommendation to DEA • Dedicated group within FDA for new drugs) • Michael Klein PhD (Director) • Serves as FDA and CDER liaison role to various components of government • Silvia Calderon PhD (Team Leader) • Provides consultation to other FDA centers regarding • Lori Love MD PhD abuse liability assessment and drug scheduling • Katherine Bonson PhD CSS matters • James Hunter RPh, MPH • Performs protocol reviews concerning pre-clinical • Morine Moody and clinical protocols • Sandra Saltz Neuroscience compounds or CNS active compounds in Phase 2 •Centrally acting •Properties that are likely to lead to misuse • PK parameters (short duration of action) • Solubility • High threshold for adverse toxicity •Continued, prolonged or excessive use leads to tolerance or dose escalation •Capable of producing dependence •FDA Draft Guidance for Assessment of Abuse Potential of Drugs (2010) High Priority Indications • Pain • Psychiatry • ADHD • Migraine • Cognitive Enhancer • Antiepileptic • Anxiolytics • Dependence treatment • Hypnotic/Sedative •Obesity • Muscle Atrophy 11 Drug Classes Historically Associated with Abuse Liability and Currently Scheduled by DEA Opioids Sedative hypnotics Cocaine, amphetamine and other CNS stimulants Hallucinogens, phencyclidine and similar agents Cannabinoids (marijuana and related compounds) Nicotine-like drugs Chemical precursors of controlled substances Anabolic steroids Drug Scheduling Process 1 Generation of preclinical and clinical data (industry) 2 Drafting of 8-Factor Analysis (industry) and finalization by FDA 3 FDA makes scientific assessment and recommends initial schedule to DEA 4 DEA schedules the new drug Approach for Identification of CNS Activity Binding Assays – Neurotransmitters historically associated with abuse potential include dopamine, norepinephrine, serotonin, GABA, nicotinic acetylcholine, opioid, NMDA, and cannabinoid receptors – Novel mechanism -- Full binding profile would be expected Routine Assays – Locomotor activity, Irwin, seizure activity, microdialysis, electrophysiology, brain imaging Question – Does the compound or a metabolite (10% plasma level of parent) reach the CNS? Revised: Preclinical Flow Chart Pharmacology / Receptor Is drug CNS active? Safety Pharm Binding Panel Profile, including LMA Physical Dependence Mechanisms with established abuse potential Mechanisms with no known evidence of abuse + signals no signals HOLD Drug Self- Discrimination Administration CPP Discussion w/ FDA Date: 8 November 2010 Preclinical Flow Chart: EMEA Guideline 2006 No Basic biochemical and in vitro and in vivo pharmacological characterisation No Novel Mechanism Signals suggesting dependence of action? potential present? Yes No Yes further non- No Insufficient information to define dependence clinical potential? testing needed Yes Drug Discrimination Behavioural assessment of dependence Studies (reinforcing properties, withdrawal syndrome) 16 Designs are tailored to the specific activity of the compound of interest. Typically these studies would be conducted in rodents as follows. PK determinations for the test compound can be verified Drug Dependence Study Repeated dosing for 2-4 weeks and evaluate signs of withdrawal from drug – including clinical signs, body weights, food intake, and other relevant assessments possible Drug Discrimination Study Train rats to discriminate training compound from vehicle in two-lever drug discrimination FR-10 paradigm. Conduct generalization dose response for training drug and new novel compound of interest Self Administration Study Rats are trained to self-administer a prototypical compound (i.e., cocaine or other compound) intravenous and then tested to determine if the new novel compound of interest will substitute in self-administration 17 Drug Dependence • Dependence phase (typically 2 weeks): test article administration daily • Withdrawal phase (typically 1 week): no test article administration • Optional Assessments • Filmed or Live Clinical Observations Clinical Observations on Ethanol Withdrawal in Male F-344 Rats Given • Body Weights BioServ® Control or Ethanol Liquid Diet for 14 Days • Food Consumption • Body Temperature • Locomotor Activity Rodent Ethanol Dependence Mean Body Weights 220.0 200.0 180.0 160.0 Control 1 (R01174) Control 2 (R01234) 140.0 1.75% EtOH (R01174) 3.5% EtOH (R01174) Body Weight (g) Body Weight 120.0 5% EtOH (R01234) 7% EtOH (R01174) 100.0 Ethanol Treatment 18 Drug Discrimination • Rats are trained to discriminate between a known reinforcing compound (CNS reference compound) and vehicle by pressing the lever associated with each condition to receive a food reward • Test articles are substituted for the CNS reference compound • Test articles that elicit a response similar the CNS reference compound may have abuse liability Amphetamine (0.3 mg/kg SC) Drug Discrimination * * 100 *p<.05 vs Vehicle, Dunnett's * 80 * * Appropriate * - 60 Responding 40 Amphetamine SC 20 Caffeine PO Methylphenidate PO % Amphetamine % 0 Vehicle 0.03 0.1 0.3 1 3 10 30 3.5 3.0 * 2.5 2.0 1.5 Responses/second 1.0 0.5 0.0 Vehicle 0.03 0.1 0.3 1 3 10 30 Dose of Drug (mg/kg) 19 Self Administration • Rats are trained to self administer a known reinforcing compound (CNS reference compound) • Test articles are substituted for the CNS reference compound and number of injections and rates of responding are compared to reference compounds Cocaine Self Administration 100 N = 8 * 80 * * 60 * 40 20 p<.05, Dunnett's Number of of Number Injections/Session 0 * 0.8 N = 8 * 0.6 * 0.4 0.2 Response Rate (Resp/sec) *p<.05, Dunnett's Figure courtsey of Tom Hudzik 0.0 Cocaine (mg/kg/injection) 20 Important Design Parameters for Abuse Liability Studies Species Selection – Rat is default Route of Administration – Dependence Oral, Drug Discrimination IP, Self-Administration – IV If IV adminisration not possible then consider other route or Conditioned Place Conditioning Dose – highest dose must produce comparable blood level
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